Native human antibodies for immune checkpoint modulation targets tim-3 and b7-h3

ABSTRACT

Novel monoclonal antibodies directed against immune checkpoint modulator (ICM) proteins TIM-3 and B7-H3 are useful in treating cancer and immune system disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.15/861,410, filed Jan. 3, 2018, which claims priority to U.S.Provisional Application No. 62/441,910, filed Jan. 3, 2017, each ofwhich is incorporated herein by reference in its entirety.

SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE

The content of the following submission on ASCII text file isincorporated herein by reference in its entirety: a computer readableform (CRF) of the Sequence Listing (file name: 12774-136US2_SeqList.txt,date recorded: May 21, 2021, size: 11 kilobytes).

TECHNICAL FIELD

The present invention relates to antibody molecules that can directlybind immune checkpoint modulator (ICM) proteins and thus regulate thefunction of an individual's immune system. More specifically, it relatesto human antibodies capable of promoting elimination of tumor cells by Tlymphocytes (T cells), Natural Killer cells (NK cells) and myeloid cellsby either reducing inhibitory signals or augmenting stimulatory signalsemanating from two ICM proteins, T cell immunoglobulin and mucin domain3 protein (TIM-3, CD366), and B7-H3 (CD276). In addition, B7-H3 has beenshown to be overexpressed in many cancers, hence direct targeting ofB7-H3 on the tumor cell can be used to eliminate the cancer. Further,the invention relates to pharmaceutical use of such agents as well as tomethods of manufacturing such agents using transfected cell lines.

BACKGROUND ART

Over the past 20 years, discovery of antibody therapeutics for cancerhas focused on proteins associated with tumor cells (also known astumor-associated antigens -TAAs-). Several such anti-tumor antibodydrugs have been commercialized, including those targeting VEGF, Her2,EGFR, and CD20. The need for an exogenous source of these antibodiesarises from the high variability in the natural immune response to tumorassociated antigens. This variability is due in part to tumor secretionof immunosuppressive factors. Over the past 5 years, a new class ofcancer therapeutics has been developed clinically that act bystimulating the immune system, thereby improving the body's naturalability to fight cancer. This class of therapeutics is known as immunecheckpoint modulators (ICM). So far, all of the drugs in this class havethemselves been antibodies, including the approved drugs Yervoy™(ipilimumab), Opdivo™ (nivolumab) and Keytruda™ (pembrolizumab) whoserespective targets are CTLA-4, PD-1 and PD-L1. These ICM antibodies workby temporarily lifting a brake on the immune system therebycounteracting tumor induced immune suppression. The ICM drugs haveproven to be particularly effective in treating melanoma, whichfrequently secretes immune suppressing factors.

Increased efficacy from combinations of these first generation ICMantibodies has been observed clinically, but accompanied by increasedtoxicity that resembles autoimmune disease. Further improvement thusdepends on identifying combinations of agents that boost anti-tumorimmunity while minimizing the adverse consequences of immune systemstimulation. Native human antibodies with ICM activity are of particularinterest in this regard, as they have been pre-selected naturally to bewell tolerated. Such native antibodies may preferentially bind toparticular ICM targets, or to particular epitopes on those targets. Morethan 20 potential ICM targets have been described in the scientificliterature. Of particular interest for the present invention areantibody molecules that bind ICM proteins TIM-3 and B7-H3.

Alternatively, B7-H3 is an appropriate TAA for antibody targetedtreatment since its expression is mainly restricted to the tumor,minimizing the risk of cytotoxicity in normal tissues. Of interest areB7-H3 antibodies that are able to mediate antibody-dependentcell-mediated cytotoxicity (ADCC). Also of interest are antibodiescapable of being internalized in the cancer cells, making themcandidates for Antibody Drug Conjugates (ADC) that can carry toxins orradioligands into the cell. Native human antibodies with anti-B7-H3activity of either type are of particular value for minimizingoff-target reactivity and rejection as a foreign protein.

U.S. Pat. No. 7,470,428 discloses the full length protein TIM-3 sequence(“Compositions and methods related to TIM-3, a Th1 specific cell surfacemolecule”). U.S. 2016/0257758 (“Antibody therapeutics that bind TIM3”);U.S. Pat. No. 8,552,156 (“Anti-TIM-3 Antibody”); U.S. 2015/218274(“Antibody molecules to TIM-3 and uses thereof”); U.S. 2016/0257749(“Anti-TIM3 antibodies and methods of use”) and U.S. 2015/0086574disclose “Antibodies binding to the Extracellular Domain (ECD) of TIM3”.The antibodies disclosed below, derived from the natural human immunerepertoire, and produced recombinantly are distinct compositions fromthese antibodies.

U.S. Pat. 2002/0198143 discloses the full length protein B7-H3 sequence(“B7-Like Polynucleotides, Polypeptides and Antibodies”). U.S.2013/0078234 (“Anti B7-H3 Antibody”) and U.S. Pat. No. 8,802,091(“Antibodies reactive with B7-H3 and uses thereof”) disclose Antibodiesbinding to the Extracellular Domain (ECD) of B7-H3. The antibodiesdisclosed below, derived from the natural human immune repertoire, andproduced recombinantly are distinct compositions from these antibodies.

DISCLOSURE OF THE INVENTION

To generate therapeutic antibodies against the broad class of candidateICM targets, we have used our previously described CellSpot technologyfor identifying rare antibodies (defined by specificity and affinity)within the memory B-cell compartment of the human immune system. Nativehuman antibodies against several ICM targets have been recovered by thismeans. Surprisingly these antibodies have been cloned from healthy blooddonors with no known cancer. In other words, the pharmacologicalapproach represented by administration of ICM antibodies appears to havea natural counterpart, consistent with the long standing immunesurveillance concept that in healthy individuals incipient tumors areeliminated by the immune system. The low frequency of memory B cellsmaking high affinity antibodies to ICM targets further suggests that thenatural ICM mechanism is transient, leaving a footprint in the memory Bcell repertoire without leading to long term autoimmune disease. Here wedescribe antibody molecules that selectively bind to either TIM-3 orB7-H3 with high affinity and specificity. These antibody molecules canbe used (alone or in combination with other agents or therapeuticmodalities) to treat, prevent and/or diagnose cancer, immune disorders,infectious disease, Crohn's disease, sepsis and other immune systemrelated health diseases.

TIM-3 is a transmembrane glycoprotein that is expressed on T cells(Monney, L., et al., Nature (2002) 415:536-541) as well as phagocyticcells such as macrophages and dendritic cells (Chiba, S., et al., Nat.Immunol. (2012) 13:832-842). TIM-3 is believed to be a negativeregulator of T cell responses. For example, binding of TIM-3 to itsputative ligand, galectin-9, on Th1 cells, results in Th1 cell death.Further, blockade of TIM-3 increases IFN-7 secreting T cells (Zhu, C.,et al., Nat. Immunol. (2005) 6:1245-1252). Additionally, co-blockade ofTIM-3 and another of its putative ligands, CEACAM1, leads to enhancementof anti-tumor immune responses with improved elimination of tumors inmouse colorectal cancer models (Huang. Y. H., et al., Nature (2015)517:386-390). Microarray analysis of hematopoietic stem cells from acutemyeloid leukemia (AML) patients and normal hematopoietic stem cellsrevealed that TIM-3 is expressed on AML stem cells. This analysissuggests the possible involvement of TIM-3 in hematological malignancy(Majeti, R., et al., Proc. Natl. Acad. Sci. (2009) 106:3396-3401).

B7-H3 is a transmembrane glycoprotein belonging to the “B7-CD28”immunoregulatory superfamily with two immunoglobulin-V-like and twoimmunoglobulin-C-like domains (e.g., IgV-IgC; Steinberger, P., et al., JImmunol. (2004) 172:2352-9). Other members of this family includeinducible co-stimulator ligand (ICOS-L), the programmed death-1 ligand(PD-L1) and, the programmed death-2 ligand (PD-L2)(Collins M., et al.,Genome Biol. (2005) 6:223), B7-H3 protein expression is tightlyregulated in healthy individuals and is not expressed on resting B or Tcells, monocytes, or dendritic cells. However, B7-H3 is induced ondendritic cells by IFN-7 and on monocytes by GM-CSF (Sharpe, A. H. andFreeman, G. J. Nat Rev Immunol (2002) 2:116-26) and is believed toinhibit Th1, Th2, or Th17 cells in vivo (Prasad, D. V., et al., JImmunol (2004) 173:2500-2506 and Yi, K. H. and Chen, L. Immunol Rev(2009) 229:145-151). Increased expression of B7-H3 on tumor cells isassociated with increased severity of disease and poorer clinicaloutcomes (Zang, X., et al., Mod. Pathol. (2010) 23:1104-1112),suggesting that B7-H3 is exploited by tumors as an immune evasionpathway (Hofmeyer. K. A. et al., Proc. Natl. Acad. Sci. USA. (2008)105:10277-8; Picarda, E. et al., Clin Cancer Res (2016) 22:3425-31).Furthermore, B7-H3 has been shown to be upregulated in many types ofcancers (while no presence was found in surrounding healthy tissues)such as: breast cancer (Arigami, T., et al., Ann. Surg. (2010)252:1044-1051); neuroblastoma (Castriconi. R., et al., Proc. Natl. Acad.Sci. USA. (2004) 101:12640-12645; Kramer, K., et al., J. Neurooncol.(2010) 97:409-418); melanoma (Wang, J., et al., J. Invest Dermatol.(2013) 133:2050-2058); gastric carcinoma (Wu, C. P., et al., World J.Gestroenterol. (2006) 12:457-459); pancreatic cancer (Yamato, I., etel., Br. J. Cancer. (2009) 101:1709-1716) and ovarian carcinoma (Zang,supra 2010). Direct target of B7-H3 alone or conjugated with a toxin orradioligand can be of interest in this regard.

Modes of Carrying Out the Invention

Human antibodies such as those disclosed here are particularly favorablefrom both an efficacy perspective (having been cloned from healthydonors) and a safety perspective (reduced chance of off-targetreactivity that would create toxicity). The frequency of humanantibodies to a particular target in the natural human repertoire istypically orders of magnitude lower than in the repertoire of immunizedmice. Accordingly, a high throughput technology capable of surveyingmillions of individual antibody producing human B lymphocytes is needed.Since human B cells have a very limited lifetime ex vivo (under 10days), the technology must also operate within that time window.

To accomplish the survey and recovery of rare favorable cells, we usedthe previously described CellSpot™ technology (U.S. Pat. Nos. 7,413,868and 7,939,344, incorporated herein by reference). This assay methodeffectively shrinks an ELLSA equivalent assay down to a virtual well ofnearly single cell dimensions by capturing secreted IgG from a singlecell as a footprint in the vicinity of the cell. In that way, 5 millionB cells can be readily analyzed. Further, by use of microscopicmultiplexing reagents (combinatorially colored fluorescent latexmicrospheres, cf U.S. Pat. No. 6,642,062, incorporated herein byreference), each clone's secreted antibody footprint can becharacterized in detail for specificity and/or affinity using multiplebiochemical probes. The fidelity of the quantitative assay is sufficientto enable rescue of extremely rare favorable cells from the surveypopulation. The cloned antibody encoding genes expressed in an exogenouscell typically show a phenotype consistent with the original identifyingassay.

The fully human antibodies of the invention are distinct from thosefound in nature, as they are prepared recombinantly. For completeantibodies, this includes constructing nucleic acids that encode ageneric form of the constant region of heavy and/or light chain andfurther encode heterologous variable regions that are representative ofhuman antibodies. Moreover, because the B cells are cultured prior toassay, mutations may arise during this ex vivo period.

As used herein, the term “antibody” includes immunoreactive fragments oftraditional antibodies and their various fragmented forms that stillretain immunospecificity such as Fab, F(ab′)₂, F_(v) fragments,single-chain antibodies in which the variable regions of heavy and lightchain are directly bound without some or all of the constant regions.Also included are bispecific antibodies which contain a heavy and lightchain pair derived from one antibody source and a heavy and light chainpair derived from a different antibody source. Similarly, since lightchains are often interchangeable without destroying specificity,antibodies composed of a heavy chain variable region that determines thespecificity of the antibody combined with a heterologous light chainvariable region are included within the scope of the invention. Chimericantibodies with constant and variable regions derived, for example, fromdifferent species are also included.

For the variable regions of mAbs, as is well known, the critical aminoacid sequences are the CDR sequences arranged on a framework whichframework can vary without necessarily affecting specificity ordecreasing affinity to an unacceptable level. Definition of these CDRregions is accomplished by art-known methods. Specifically, the mostcommonly used method for identifying the relevant CDR regions is that ofKabat as disclosed in Wu. T. T., et al., J. Exp. Med. (1970) 132:211-250and in the book Kabat. E. A., et al. (1983) Sequence of Proteins ofImmunological Interest, Bethesda National Institute of Health, 323pages. Another similar and commonly employed method is that of Chothia,published in Chothia, C., et al., J. Mol. Biol. (1987) 196:901-917 andin Chothia, C., et al., Nature (1989) 342:877-883. An additionalmodification has been suggested by Abhinandan, K. R., et al., Mol.Immnunol. (2008) 45:3832-3839. The present invention includes the CDRregions as defined by any of these systems or other recognized systemsknown in the art.

The specificities of the binding of the mAbs of the invention aredefined, as noted, by the CDR regions mostly those of the heavy chain,but complemented by those of the light chain as well (the light chainsbeing somewhat interchangeable). Therefore, the mAbs of the inventionmay contain the three CDR regions of a heavy chain and optionally thethree CDR's of a light chain that matches it. Because binding affinityis also determined by the manner in which the CDR's are arranged on aframework, the mAbs of the invention may contain complete variableregions of the heavy chain containing the three relevant CDR's as wellas, optionally, the complete light chain variable region comprising thethree CDR's associated with the light chain complementing the heavychain in question. This is true with respect to the mAbs that areimmunospecific for a single epitope as well as for bispecific antibodiesor binding moieties that are able to bind two separate epitopes.

Bispecific binding moieties may be formed by covalently linking twodifferent binding moieties with different specificities. Multipletechnologies now exist for making a single antibody-like molecule thatincorporates antigen specificity domains from two separate antibodies(bi-specific antibody). Suitable technologies have been described byMacroGenics (Rockville, Md.). Micromet (Bethesda, Md.) and Merrimac(Cambridge, Mass.). (See, e.g., Orcutt, K. D., et al., Protein Eng. Des.Sel. (2010) 23:221-228; Fitzgerald. J., et al., MAbs. (2011) 1:3;Baeuerle, P. A., et al., Cancer Res. (2009) 69:4941-4944). For example,the CDR regions of the heavy and optionally light chain derived from onemonospecific mAb may be coupled through any suitable linking means topeptides comprising the CDR regions of the heavy chain sequence andoptionally light chain of a second mAb. If the linkage is through anamino acid sequence, the bispecific binding moieties can be producedrecombinantly and the nucleic acid encoding the entire bispecific entityexpressed recombinantly. As was the case for the binding moieties with asingle specificity, the invention also includes the possibility ofbinding moieties that bind to one or both of the same epitopes as thebispecific antibody or binding entity/binding moiety that actuallycontains the CDR regions. The invention further includes bispecificconstructs which comprise the complete heavy and light chain sequencesor the complete heavy chain sequence and at least the CDR's of the lightchains or the CDR's of the heavy chains and the complete sequence of thelight chains.

The mAbs that are the subject of the present invention are not isolatedfrom human blood or plasma, but rather are recombinantly produced. Inbrief, human blood cells that secrete antibodies are assessed toidentify those cells that secrete mAbs of appropriate specificity andaffinity. The RNA or DNA encoding these antibodies is extracted from thecells thus identified and the variable regions cloned. The resulting DNAencoding the heavy and light chain variable regions is coupled to DNAencoding generic constant regions and the resulting recombinant DNAencoding the complete antibody in each case is provided with controlsequences to effect expression and secretion of the recombinant mAbs.Alternatively, the variable regions may be directly employed to encode,for example, single-chain forms of the mAbs. Suitable control sequencesand secretion signal encoding sequences are well known in the art as aremethods for recombinant production of encoding nucleic acids.

The mAbs of the invention are thus recombinantly produced using knowntechniques. The invention also includes nucleic acid moleculescomprising nucleotide sequence encoding them, as well as vectors orexpression systems that comprise these nucleotide sequences, cellscontaining expression systems or vectors for expression of thesenucleotide sequences and methods to produce the binding moieties byculturing these cells and recovering the binding moieties produced. Anytype of cell typically used in recombinant methods can be employedincluding prokaryotes, yeast, mammalian cells, insect cells and plantcells. Also included are human cells (e.g., muscle cells or lymphocytes)transformed with one or more recombinant molecules that encodes thenovel antibodies.

Typically, expression systems for the mAbs of the invention include oneor more nucleic acids encoding said at least the variable regionscoupled to control sequences for expression. In many embodiments, thecontrol sequences are heterologous to the nucleic acid encoding theprotein. The invention is also directed to nucleic acids encoding thebispecific moieties and to recombinant methods for their production, asdescribed above.

Thus, typically the nucleic acids encoding the mAbs or antigen-bindingportions thereof are comprised in vectors that include expressionsystems for said encoding nucleic acids, which vectors are functional intransforming recombinant host cells for the production of the desiredmAb or antigen-binding portion.

The invention is also directed to pharmaceutical and veterinarycompositions which comprise as active ingredients the antibodies of theinvention. The compositions contain suitable physiologically compatibleexcipients such as buffers and other simple excipients. The compositionsmay include additional active ingredients as well, in particularanti-tumor chemotherapeutic agents. The binding moieties of theinvention may also be used in diagnosis.

The following examples are offered to illustrate but not to limit theinvention.

EXAMPLE 1

Human blood from anonymized donors from the Stanford Blood Center,obtained under informed consent, were screened for six ICM targets,including TIM-3 and B7-H3. The cells were subjected to the CellSpot™assay to determine their ability to bind the antigens. The CellSpot™assay is described in U.S. Pat. Nos. 7,413,868 and 7,939,344. Afterisolating Human peripheral blood mononuclear cells (PBMC's), they werestimulated with cytokines and mitogens to initiate a brief period ofmemory B cell proliferation, differentiation and antibody secretion(lasting 5 days) and plated for subjection to the assay. The encodingnucleic acids for the variable regions of positive antibodies wereextracted and used to produce the antibodies recombinantly by cloningthe DNA in expression vectors containing a signal peptide as well as theconstant region for the heavy and light chains.

EXAMPLE 2

The TIM-3 antibody molecules of the present invention were clonedfollowing a survey of 22 blood donors for binding to 6 different ICMantigens, including the extracellular domain (ECD) of TIM-3. Anti-TIM-3antibodies were detected in 15 of the donors at different frequencies(Table 1 and 2). BSA was used as a counterscreen to eliminatepolyreactive antibodies. Four mAbs were cloned.

TABLE 1 Frequencies of anti-TIM-3 CellSpot ™'s in all doors tested DonorTIM-3 # CellSpot ™'s/100K Memory Cells SBC207 0.3 SBC210 0.2 SBC222 0SBC223 2.7 SBC224 0 SBC230 0.6 SBC235 1.2 SBC236 0.4 SBC238 2.8 SBC2401.6 SBC241 0 SBC243 0 SBC246 0.3 SBC248 0.6 SBC251 0 SBC252 0 SBC254 0.1SBC255 0.4 SBC256 0 SBC258 1.4 INF 6.11 0.6 INF 4.2 1.9

TABLE 2 Donors for Trellis Anti-TIM-3 antibodies TIM-3 TRLmAb Donor #6042 236 6061 207 6099 254 6120 238

Purified mAbs were tested in adsorption ELISA using TIM-3 ECD, generatedby Trellis in mammalian cells. Serial dilutions allowed calculating anestimate of the binding affinities (values listed in Table 3 areexpressed as nM). TRL6061 and 6099 are of particular interest based onits sub-nM affinity to the target. A diverse set of germline variableregions was found in this group of mAbs as seen in Table 4.

TABLE 3 Affinities for Trellis Anti-TIM-3 TIM-3 TRLmAb Affinity (nM)6042 5 6061 0.005 6099 0.011 6120 28

TABLE 4 Germlines for Trellis Anti-TIM-3 antibodies TIM-3 TRLmAb VHgermline VL germline 6042 IGHV5-51*01 IGKV1-9*01 6061 IGHV3-33*01IGLV3-10*01 6099 IGHV3-38*01 IGLV1-44*01 6120 IGHV3-33*01 IGLV3-10*01

Sequences of Trellis anti TIM-3 VH and VL in amino acids:

TRL6042 VH (SEQ ID NO: 1)qvglvesgaevkkpgeslkiscegsgykftsywigwvrqmpgrgpewmgliypsdsdtryspsfrgvtisvdktistaylqwsslktsdtaiyycarlllatectsdscfgdafdiwgqgtmvtvss TRL6042 VL (kappa) (SEQ. ID NO: 2)divltqsptflsasvgdrvtitcrasqgissylawyqqkpgkapklllyaastlgsgvpsrfsgsrsgteftltisslqpedfasyycqqfhnypftfgggt kveikr TRL6061 VH(SEQ ID NO: 3) qvqlvesgggvvqpgrslrlscaasgfmfstsamhwvrqtpgkglewlaviwhdgsekyyadsvkgrfsisrdnyrdtlylqmnnlrvedtaiyycrggdvy eiwgqgtmvavssTRL6061 VL (lambda) (SEQ ID NO: 4)ddimltqppsvsvspgqtaritcsgdavakryvywyqqksgqapvlvmyednkrpsgiperfsgsssgtkatltitgalvedeadyycystdssgnlgafgg gskltvl TRL6099 VH(SEQ ID NO: 5) qvglvesgaevkkpgasvkvsckafnytftsygiswvrqtpehglewmgwitnsnsnsaqkfqgrvsmttdtststaymqlrslssddtavyycariyidyn nygldvwgqgttvtvssTRL6099 VL (lambda) (SEQ ID NO: 6)divltqspsasgtpgqrviiscsgsssniggntvnwyqqlpgtapklliysndqrpsgvpdrfsgsksgtsaslaisglqsedeadyycaawddslsgpafg ggtkltvlg TRL6120 VH(SEQ ID NO: 7) qvqlvesgggvvqpgrslrlscvasgfifrtyamhwvrqapgkglewvaviwpdgseryysdstkgrftvsrdnskntlflqmnslrvddtamyycfargys dsdyadhwgrgtrvtvssTRL6120 VL (lambda) (SEQ ID NO: 8)divmtqspsvsvspgqtaritcsgdalstkfaywyqqksgqapvlviyednkrpsgiperfsgsgsgtmatlgvseaqvedeadyycfssdssgnlfmfggg tkltvl

EXAMPLE 3

The B7-H3 antibody of the present invention was cloned following asurvey of 14 blood donors for binding to 6 different ICM antigens,including the ECD of B7-H3. Anti-B7-H3 antibodies were detected in only3 of the donors at low frequencies (Tables 5 and 6), suggesting thatthese antibodies are rarer than anti-TIM-3 antibodies in healthy donors(Table 1). BSA was used as a counterscreen to eliminate polyreactiveantibodies. One antibody was cloned.

TABLE 5 Frequencies of anti-B7-H3 CellSpots in all doors tested DonorB7-H3 # CellSpot ™'s/100K Memory Cells SBC224 0 SBC227 0 SBC232 0 SBC2340.8 SBC235 0.3 SBC237 0 SBC238 0 SBC238 0.5 SBC243 0 SBC247 0 SBC254 0SBC255 0 AC1628 0 AC1681 0

TABLE 6 Donors for Trellis Anti-B7-H3 antibody TIM-3 TRLmAb Donor # 4542254

Purified mAb was tested in adsorption ELISA using B7-H3 ECD, generatedby Trellis in mammalian cells. Serial dilutions allowed calculating anestimate of the binding affinities (value listed in Table 7 is expressedas nM). In Table 8 is shown the germlines for the heavy and light chainvariable regions.

TABLE 7 Affinities for Trellis Anti-B7-H3 antibody B7-H3 TRLmAb Donor #4542 5

TABLE 8 Germlines for Trellis Anti-B7-H3 antibody B7-H3 TRLmAb VHgermline VL germline 4542 IGHV3-15*01 IGKV4-1*01

Sequences of Trellis Anti-B7-H3 VH and VL in amino acids:

TRL4542 VH (SEQ ID NO: 9)qvqlvesggdlvqpgeslrlscaasgfifsdawmvwvrqapgkglewvgriktngdggttdltepvkgrftisrddsknmvylqmnnlrtedtaiyycttap gfwgqgtlvtvss TRL4542 VL (kappa) (SEQ ID NO: 10)diemtqspdslavslgeratincksshnllyksnnknylawsqqkpgqpprlliywastrdsgvpdrfsgsgsgtdftltisslqaedvayychqyygtkwt fgqgtrveikr

1. An isolated nucleic acid or isolated nucleic acids that separately orin combination encode a recombinantly produced monoclonal antibody (mAb)or effective antigen-binding portion thereof, which includes the CDRregions of TRL6042, TRL6061, TRL10006, TRL6099, TRL6120 or TRL4542. 2.The nucleic acid or nucleic acids of claim 1 coupled to controlsequences for expression.
 3. The nucleic acid or nucleic acids of claim2 contained in a vector.
 4. Host cells containing a vector of claim 3.